This program is focuses on mechanisms of inflammatory lung injury. Considerable emphasis will be placed on the interlocking roles of cytokines, adhesion molecules (both leukocytic and endothelial) and recruitment of inflammatory cells (neutrophils, and mononuclear leukocytes) in lung. Project I (Ward) deals with the relationship between cytokines (TNFalpha, IL-1, MCP-1), upregulation of endothelial adhesion molecules (ICAM-1, VCAM-1, P-and E-selectins), and recruitment of leukocytes into lungs containing IgG or IgA immune complexes. The requirements of L-selectin will also be assessed. The regulatory functions of IL-4 and IL-10 will be studied in the inflammatory models. Transgenic mice (expressing intrapulmonary C5a or in the murine homologue of IL-8, KC) as well as C5a receptor and KC receptor "knockout" mice will be studied, using similar inflammatory models of lung injury. Project II (Kunkel) deals with granulomatous lung inflammation and the roles of early response gene products (TNFalpha, IL-1) in adhesion molecule dependent (ICAM-1, VCAM-1) recruitment of leukocytes, and the activation of these recruited cells for naturally occurring antagonists (IL-1 receptor antagonist, soluble TNF receptor-1) will be employed to address these issues. Project III (Warren) deals with the in vivo and in vitro roles of cytokines (TNFalpha, IL-1) in regulating the expression of monocyte-relevant adhesion molecules (E-selection, ICAM-1, VCAM-1) and the recruitment of monocytes in models of pulmonary vasculitis. Project IV (Phan) deals with the regulation of MCP-1 gene expression in bleomycin-treated lungs undergoing fibrotic changes and identification of MCP-1 gene expression in bleomycin-treated lungs undergoing fibrotic changes and identification of the lung cells responsible got MCP-1 expression. The role of MCP-1 in pulmonary fibrosis will also be determined by the used of a blocking antibody. Project V (stoolman) explores the roles of integrins, selections and cellular activation during mononuclear leukocyte adhesion to activated endothelium under conditions of shear-stress. The upregulation of alpha4-integrin function and its role in mediating selection-int adhesion is the principal focus. Hypotheses based on in vitro modeling of mononuclear leukocyte- endotheesion will be tested in two models of granulomatous inflammation. Mononuclear leukocytes recruitment will be assessed in lung models of inflammation and the effects of cytokines and VCAM-1 in these events determined. Core A (Ward) will provide administrative support and scientific leadership while Core B (Johnson) will provide morphological, morphomeic and medical illustration support. This project should provide important information related to mechanisms of lung inflammatory injury.